The Caltech-Boulder-Targacept National Cooperative Drug Discovery and Development Group (NCDDDG) continues to be motivated by the hypothesis that successful smoking cessation compounds can selectively target just one or a few nicotinic acetylcholine receptor (nAChR) combinations. Nicotine addiction begins with the activation of these receptors, which are ligand-gated channels. Progress in this NCDDG and around the world during the 2005-2010 Project Period provided additional knowledge about the range of homo- and hetero-pentameric subtypes that do exist in the brain;about their localization;and about their specific roles in the constellation of phenomena that comprise nicotine addiction (tolerance, dependence, sensitization, and goal-seeking behavior). Nonetheless, knowledge remains partial, especially about the long-term effects of both nicotine and smoking cessation drugs. The 2010-2015 Project Period provides an iterative series of experiments to test hypotheses in these areas. (1) The NCDDDG will use accumulating knowledge to optimize lead compounds for smoking cessation. We will devote the first 2 yr of the Project Period to three lead compounds that emphasize a6-oriented and/or a4-oriented activity: varenicline, TCD-1010, and one other compound to be chosen by the Executive Committee. The compounds are expected to exhibit varying ratios of a6* to a4* activity. All these compounds will be at least partial agonists. We expect that all compounds will also desensitize a4* nAChRs;a6* desensitization will be studied in detail in Project 3. (2) It is also likely that successful smoking cessation compounds will themselves produce long-term changes in these target nAChRs. Therefore Projects 2 and 3 will use mouse models to explore possible upregulation, an adaptive change in nAChRs caused by chronic exposure to lead compounds. (3) The iterative experiments will, in turn, lead to synthesis of new compounds at Targacept (Project 1), and further testing during the final three yr of the 2010-2015 Project Period. This scientific approach will enable the Group, as well as other groups throughout the world, to optimize and develop lead compounds for smoking cessation. (4) While pursuing these goals in parallel, we intend to continue publishing all of our studies according to the usual standards that have characterized research in academic neuroscience.